The general objective of this project is to use a number of animal and cell culture systems to study the link between insulin binding to its cell surface receptor and the regulation of specific metabolic enzymes. The system to be used includes intact and chemically-induced diabetic rats, genetically diabetic mice and normal litter mates, isolated hepatocytes from each of these, and hepatoma tissue culture cell lines. The insulin receptor will be characterized on each of these and attempts to regulate receptor concentration will be made. The enzymes to be studied are tyrosine aminotransferase, phosphoenolpyruvate carboxykinase, malic enzyme and glucokinase. We will study the effects of insulin, related hormones, and dibutyryl cyclic AMP on the enzymic activity, the in vivo synthesis and mRNA activity of these proteins. Such studies should help establish the connection between receptor binding and the regulation of specific protein synthesis.